Palladium-catalyzed allylation and deacylative allylation of 3-acetyl-2-oxindoles with allylic alcohols

Article abstract of DOI:10.1016/j.tet.2017.11.041

The Pd-catalyzed allylation of 3-acetyl-2-oxindoles with allyl alcohol is performed using 3 mol% of Pd(dba)₂, rac-BINAP and BINOL phosphoric acid as catalytic mixture. This procedure allows the in situ synthesis of 3-allyl-2-oxindole by adding

Full text of DOI:10.1016/j.tet.2017.11.041

Accepted Manuscript
Palladium-catalyzed allylation and deacylative allylation of 3-acetyl-2-oxindoles with
allylic alcohols
Aitor Ortega-Martínez, Rocco de Lorenzo, José M. Sansano, Carmen Nájera
PII:
S0040-4020(17)31189-4
10.1016/j.tet.2017.11.041
TET 29121
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 October 2017
Revised Date: 13 November 2017
Accepted Date: 14 November 2017
Please cite this article as: Ortega-Martínez A, de Lorenzo R, Sansano JoséM, Nájera C, Palladium-
catalyzed allylation and deacylative allylation of 3-acetyl-2-oxindoles with allylic alcohols, Tetrahedron
(2017), doi: 10.1016/j.tet.2017.11.041.
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Palladium-catalyzed allylation and deacylative
allylation of 3-acetyl-2-oxindoles with allylic
alcohols
Aitor Ortega-Martínez, Rocco de Lorenzo, José M. Sansano,* and Carmen Nájera*

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Palladium-catalyzed allylation and deacylative
allylation of 3-acetyl-2-oxindoles with allylic
alcohols
Aitor Ortega-Martínez, Rocco de Lorenzo, José M. Sansano,* and Carmen Nájera*
O
R3
Pd(dba)2/BINAP (3 mol%)
O
O
R4
N
R1
R2
R2 = H
BINOL-phosphoric acid
(3 mol%)
R3
R4
R4
OH
O
+
R4
Pd(OAc)2/dppp (3 mol%)
N
R1
R4
R2 = Me
R3
LiOtBu (1.5 eq)
R4
O
DaA
N
R1

1
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Tetrahedron
journal homepage: www.elsevier.com
Palladium-catalyzed allylation and deacylative allylation of 3-acetyl-2-oxindoles with
allylic alcohols
a,b
a,b
a,b
a
Aitor Ortega-Martínez, Rocco de Lorenzo, José M. Sansano, * and Carmen Nájera *
a
Department of Organic Chemistry and Centro de Innovación en Química Avanzada (ORFEO-CINQA). Faculty of Sciences, University of Alicante, E-03080
Alicante, Spain. Fax: +34 965903549
b
Instituto de Síntesis Orgánica, University of Alicante.
E-mail: jmsansano@ua.es, cnajera@ua.es
ARTICLE INFO
ABSTRACT
Article history:
Received
The Pd-catalyzed allylation of 3-acetyl-2-oxindoles with allyl alcohol is performed using 3 mol% of
Pd(dba) , rac-BINAP and BINOL phosphoric acid as catalytic mixture. This procedure allows the in
2
Received in revised form
Accepted
situ synthesis of 3-allyl-2-oxindole by adding Triton B to the reaction mixture. The deacylative
allylation of 3-acetyl-3-methyl-2-oxindoles with allylic alcohols is carried out with 3 mol% of
Available online
2
Pd(OAc) , dppp and 1.5 equiv. of LiOtBu as base affording the corresponding 3,3-disubstituted 2-
oxindoles in good yields. Both methodologies can be combined for the preparation of unsymmetrical
3,3-diallylated 2-oxindoles such as compound 7. The DaA must be carried out in the absence of
oxygen in order to avoid the competitive formation of 3-alkyl-3-hydroxy-2-indoles. The later
compounds can be easily obtained by deacylative oxidation of 3-alkylated 3-acetyl-2-oxindoles with
LiOEt at rt under air.
Keywords:
oxindoles
allylic alcohols
palladium
catalysis
2
017 Elsevier Ltd. All rights reserved.
deacylation

2
Tetrahedron
ACCEPTED MANUSCRIPT
1
. Introduction
Pd-catalyzed allylation of nucleophiles with allylic alcohols is
For the Pd-catalyzed synthesis of 3-allyl-2-oxindoles, two
alternative methodologies have been described: (a) one
intramolecular process based on the Meerwein−Eschenmoser
1
a direct methodology for the formation of C-C bonds. Allylic
alcohols are commercially available compounds and their direct
use avoids the preparation of their derivatives, normally acetates,
carbonates and phosphates, to generate the corresponding π-allyl
Pd electrophilic intermediates. Due to the poor leaving group
ability of the OH group it has to be activated by means of Lewis
or Brønsted acids or by forming in situ the corresponding esters.
Alternatively, two main strategies can be used for the Pd-
catalyzed allylation of active methylene derivatives: (a)
10
Claisen rearrangement of 2-allyloxyindoles ; (b) direct allylic
alkylation of oxindoles with simple allylic alcohols co-
11a
catalyzed by Pd(OAc) /Ph P and PhCO H; and c) the DaA of
3
2
3
2
11b
-acyl-2-oxindoles with allylic alcohols (Scheme 2).
2
decarboxylative allylation (DcA) of allyl esters and (b)
3
deacylative allylation (DaA) with allylic alcohols of acylated
substrates (Scheme 1). Intramolecular DcA requires an anion
stabilizing group for the decarboxylative metalation of the
starting allyl esters, which has to be previously formed by
4
transesterification with Otera’s catalyst (XR SnOSnR X) using a
2
2
large excess of the allylic alcohol. Intermolecular deacylative
metalation needs the introduction of the acetyl or a carboxylate
group, which react with the alcoholate under basic conditions
generating, in situ, the acetate or carbonate, respectively. This
DaA takes place in THF or DMSO at 60 ºC and has been studied
with α-nitro and α-cyano ketones, 1,3-diketones, and α-
cyanoacetates.
Scheme 2. Synthesis of 3-allyl-2-oxindoles by Pd-catalyzed methodologies
We have recently described the synthesis of 3,3-disubstituted
2
-oxindoles by deacylative alkylation of 3-acetyl-2-oxindoles
Scheme 1. Pd-Catalyzed allylation of active methylene compounds by DcA
and DaA
with alkyl halides and electrophilic alkenes under basic
12
conditions. Independently, Bisai and co-workers published a
palladium-catalyzed allylation of 3-acetyl-2-oxindoles during the
11b
elaboration of this manuscript. Herein, we report our findings
about the synthesis of 3,3-disubstituted 2-oxindoles by Pd-
catalyzed direct allylation of 3-acetyl-2-oxindoles and by
deacylative allylation. The main objectives of this study are: a)
evaluate the possible palladium-catalyzed monoallylation of 3-
acetyl-1-methyl-2-oxindole 1a; b) study the DaA using similar
conditions from 3-acetyl-1,3-methyl-2-oxindole (4a); c) the
oxidation of heterocycles 4 under a mild process avoiding
oxidizing agents.
3
,3-Disubstituted 2-oxindoles are important class of
heterocyclic compounds occurring in natural alkaloids and
biologically active compounds, for instance the alkaloid
horsfiline and also esermethole, which is an intermediate for the
synthesis of acetylcholinesterase inhibitors physostigmine and
phenserine (Figure 1). This family of compounds have been
synthetized from 3-allyl-3-methyloxindoles. The Pd-catalyzed
prenylation and geranylation of 3-substituted 2-oxindoles has
been performed with the corresponding allylic carbonates of the
5
6
7
8
9
monoalkylated oxindole. The resulting compounds are synthetic
intermediates of flustramides A and B with skeletal and smooth
muscle relaxant activity.
2
. Results and Discussion
Initially studies about the allylation of 3-acetyl-1-methyl-2-
oxindole (1a) were performed with allyl alcohol in the presence
Me
Me
N
12
X
N
MeO
MeO
Me
of different additives (Table 1). The selection of the N-
methylated structure obeyed to this arrangement is present in
many natural compounds (Figure 1). Using the Tamaru reaction
H
O
O
N
N
N
Me
R
H
esermethole: X = OMe
1
3
horsfiline
physostigmine: X = OCONHMe
phenserine: X = OCONHPh
conditions for the allylation of active methylene compounds,
mol% of Pd(OAc)2 and 1,3-bis(diphenylphosphino)propane
dppp), in the presence of triethylborane (60 mol%), gave
3
(
compound 2aa in 99% isolated crude yield (Table 1, entry 1). In
order to diminish the amount of additive 3 mol% of p-
O
O
NC
N
N
toluenesulfonic acid (TsOH) was employed instead of Et B
Me
Me
3
O
H
N
H
Br
N
Br
affording 2aa in only 3% yield (Table 1, entry 2). Next, Pd(dba)
was employed instead of Pd(OAc) without success (Table 1,
2
N
Br
H
2
entry 3). However, by changing the dppp ligand by rac-BINAP
product 2aa was obtained in 66% yield (Table 1, entry 4). Using
rac-BINOL phosphoric acid instead of TsOH gave a 98% of
product 2aa (Table 1 entry 5). These reaction conditions: 3 mol%
rac-flustramide A
rac-flustramide B
Figure 1. Biologically active 3,3-disubstituted oxindoles

3
of Pd(dba) /rac-BINAP//rac-BINOL phosphor
rt, were used for the allylation of 3-acetyl-2-oxindoles 1b and 1c
providing the corresponding allylated compounds 2ba and 2ca in
A
ic
C
ac
C
id
E
in
P
T
T
H
E
F
D
at MA(T
N
ab
U
le
S
2)
C
. U
R
si
I
ng Pd(OAc) and dppp (3 mol%) as catalysts and
2
P
T
2
KOtBu (1.1 equiv) as base in THF, after 15 h at rt under Ar
atmosphere, a 3:1 mixture of 5ab and also the oxidized 3-
hydroxy-1,3-dimethyl-2-oxindole 6aa were obtained, compound
5ab being isolated after flash chromatography in 54% yield
(Table 2, entry 1). The same process was repeated in the absence
of oxygen (freezing-pump) and using LiOtBu instead of KOtBu
giving a 95:5 mixture of both products, but also a 17% of 1,3-
dimethyl-2-oxindole (3aa) (Table 2, entry 2). After increasing the
amount of dppp to 6 mol% a 60:40 mixture of product 5ab and
6
1 and 89% yield, respectively (Table 1, entries 6 and 7). To the
best of our knowledge, this is the first palladium-catalyzed
allylation of 3-acetyl-1-methyl-2-oxindoles from allyl alcohol.
Table 1. Pd-Catalyzed allylation of 3-acetyl-2-oxindoles
3
aa was formed (Table 2, entry 3). Changing Pd(OAc)2 by
Pd (dba) increased the amount of deacetylated product (Table 2,
2
3
entry 4). Finally increasing the amount of LiOtBu to 1.5 equiv
the formation of a mixture of 86% of the expected product 5ab
together with 10% of 3aa and only 3% of 6aa was observed
(
Table 2, entry 5).
Table 2. Reaction conditions study for the Pd-catalyzed DaA of
a
3
-acetyl-1-methyloxindole (4a).
Cat (3
mol%)
Ligand
(3 mol%)
Additive
(mol%)
Yield
(%)
Ent.
2
b
nC3H7
O
O
N
1
2
3
4
5
6
7
Pd(OAc)
2
2
dppp
Et
3
B (60)
2aa
2aa
2aa
2aa
99
3
[Pd]/dppp
Me
5ab
(3 mol%)
Pd(OAc)
dppp
TsOH (3)
TsOH (3)
TsOH (3)
O
N
Base, THF
rt
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
2
dppp
-
OH
Me
2
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
66
4a
O
O
c
N
N
2
2
2
(BINOL)PO
(BINOL)PO
(BINOL)PO
2
2
2
H (3) 2aa
98 (96)
91 (61)
99 (89)
nC H
OH
Me
aa
3
7
Me
6aa
c
H (3) 2ba
3
c
H (3) 2ca
a
Reaction conditions: 1 (0.3 mmol), allyl alcohol (0.45 mmol), Pd
(
3 mol%), ligand (3 mol%), additive (see column), THF (1.5 mL),
0 h.
Isolated crude yield. In parenthesis, yield after flash chromatography.
2
Racemic (BINOL)PO H was employed.
Cat (3
mol%)
b
Yield
(%)
Entry
Base (equiv)
Products ratio (%)
c
6
b
d
c
1
Pd(OAc)
2
2
KOtBu (1.1)
LiOtBu (1.1)
LiOtBu (1.1)
LiOtBu (1.1)
LiOtBu (1.5)
5ab (76), 6aa (24)
54
66
-
e
2
Pd(OAc)
5ab (79), 3aa (17), 6aa (4)
5ab (61), 3aa (39)
e
f
3
Pd(OAc)
2
e
g
4
Pd
2
(dba)
3
5ab (49), 3aa (51)
5ab (86), 3aa (10), 6aa (3)
-
e
The synthesis of 3-allyl-1-methyl-2-oxindole (3ab) was
carried out by in situ addition of solution of
benzyltrimethylammonium hydroxide (Triton B) (40% in MeOH)
1 equiv) followed by addition of AcOH (0.85 mL) in 61% yield
Scheme 3). Attempts to prepare this compound by allylation of
5
Pd(OAc)
2
70
a
a
Reaction conditions: 4a (0.3 mmol), allyl alcohol (0.45 mmol), Pd (3
mol%), ligand (3 mol%), THF (1.5 mL), 15 h, argon atmosphere.
Determined by 300Mhz H NMR on the crude product.
Isolated crude yield. In parenthesis, yield after flash chromatography.
Without using freezing pump.
After using freezing pump.
mol% dppp was used.
.5 mol% of Pd (dba) was used
b
c
d
e
f
1
(
(
N-methyl-2-oxindole with allyl bromide and Triton B as base
12
6
1
gave the corresponding 3,3-diallylated 2-oxindole. Therefore,
this one-pot procedure can be used for the synthesis of 3-
monoallylated oxindoles instead of using LiHMDS at -78 °C
during the allylation of N-alkyloxindole or sodium hydride at
g
2
3
For the scope studies of this DaA process, different
substituted oxindoles 4 and allylic alcohols were assayed using
14
different temperatures.
the optimal reaction conditions described on Table 2, entry 5 but
1
7 h instead of 15 h were needed as reaction time (Table 3). The
reaction of 4a with primary allylic alcohols such as allyl alcohol,
hex-2-enol and methallyl alcohol gave the corresponding
products 5aa, 5ab and 5ac in good yields (Table 3, entries 1-3).
The same occurred with geraniol giving product 5af in moderate
4
5% yield (Table 3, entry 6). However, 1-methylallyl alcohol
afforded a ca. 2:1 inseparable mixture of the γ- and the α-
allylated products 5ad and 5ad’ in 45% overall yield (Table 3,
entry 4). Similar results were observed with prenyl alcohol
affording a separable mixture of γ- and α-products 5ae and 5ae’
in 51% and 16% yields, respectively (Table 3, entry 5). In the
case of pent-1,4-dien-3-ol, a 8:1 mixture of γ- and α-products
5ag and 5ag’ was obtained in 62% overall yield (Table 3, entry
7). The DaA of 4a with cyclohex-2-ol gave dialkylated 2-
Scheme 3. One-pot synthesis of 3-allyl-1-methyl-2-oxindole (3ab).
Next, the Pd-catalyzed deacylative allylation of 3-acetyl-1,3-
methyl-2-oxindole (4a) was attempted. The reaction conditions
12
study was carried out with compound 4a and hex-2-en-1-ol

4
Tetrahedron
oxindole 5ah in 75% yield as a 1:1 mixture
Table 3, entry 8). Primary alcohols such as (−)-myrtenol and
cinnamyl alcohol provided compounds 5ai and 5aj in 56 and
A
o
C
f d
C
ia
E
ste
P
re
T
o
E
me
D
rs MAdi
NU
ast
ere
S
o
C
me
R
rs
I
.
P
Reactions of allyl alcohol with oxindoles 4b and
T
(
4c gave the corresponding products 5ba and 5ca in 72% and 77%
yields, respectively (Table 3, entries 11 and 12). It is remarkable
that compounds 5ab, 5ad, 5af, 5ag and 5aj were isolated as
unique E-stereoisomers.
5
1% yields, respectively (Table 3, entries 9 and 10). Compound
5
ai was obtained as an inseparable 5.5:1 mixture of
a
Table 3. Palladium-catalyzed DaA of 3-acetyl-2-oxindoles 4.
b
Entry
4
Allylic Alcohol
No.
5aa
5ab
5ac
Product
Yield (%)
1
2
3
4a
4a
4a
80
70
74
5
ad
OH
c
4
4a
45
5
ad’
4
a
5
5ae
51
16
O
N
Me
5
ae’
4
a
6
5af
45

5
ACCEPTED MANUSCRIPT
d
5
ag
55
7
4a
5
ag’
7
O
N
Me
4
4
a
a
e
8
9
5ah
75
f
5ai
5aj
56
g
4a
Ph
OH
1
0
51
4
b
1
1
5ba
5ca
72
77
4
c
1
2
a
2
Reaction conditions: 4 (0.3 mmol), allylic alcohol (0.45 mmol), Pd(OAc) (3 mol%), dppp (3 mol%), LiOtBu (0.45 mmol),
THF (1.5 mL), 17 h at rt under argon atmosphere using freezing-pump.
b
Isolated yields after flash chromatography
c
An inseparable mixture of compounds 5ad (68%) and 5ad’ (32%) was obtained.
A 8:1 mixture of compounds 5ag and 5ag’ was obtained.
A ca. 1:1 mixture of diastereomers was obtained.
d
e
f
A 5.5:1 mixture of diastereomers was obtained.
g
24 h reaction time.
The synthesis of the unsymmetrically disubstituted 3,3-
diallylated oxindole 7 was performed first by allylation of 1a
affording product 2aa followed by Pd-catalyzed deacylative
allylation with methallyl alcohol affording product 7 in 72%
overall yield (Scheme 4).
Scheme 4. Sequential synthesis of 3-allyl-3-methallyl-1-methyl-2-oxindole
(7).

6
Tetrahedron
as MAN
The formation of 3-hydroxy-1,3-dimeth
A
yl-
C
2-
C
ox
E
in
P
do
T
le
E
s
D
M
U
el
S
tin
C
g
R
po
I
i
P
nt was determined with a Marienfeld melting point
T
secondary products when oxygen was presented in the medium
prompt us to study the best reaction conditions for the synthesis
of 3-hydroxy oxindoles. 3-Substituted-3-hydroxy-2-oxindoles are
important structural components of pharmacological active
alkaloids such as convolutamydines and other useful
intermediates for the synthesis of biological active compounds.
For the synthesis of these type of compounds 3-substituted-2-
oxindoles together with oxygenating reagents are used. Bisai
meter (MPM-H2) apparatus and are uncorrected. For flash
chromatography, silica gel 60 (40-60 µm) was employed. 300
1
13
and 400 MHz H NMR and 75 and 101 MHz C NMR (spectra
were recorded using Bruker AV300 and Bruker AV400,
respectively, with CDCl as solvent and TMS as internal standard
3
15
1
13
for H NMR, and the own chloroform signal for C NMR, and
chemical shifts are given in ppm. IR spectra were recorded using
a Jasco FT/IR-4100 Fourier Transform Infrared Spectrometer and
a Nicolet Avatar 320 FT-IR Spectrometer. Low-resolution
electron impact (GC-EI) mass spectra were obtained at 70 eV
using a Agilent 6890N Network GC system and Agilent 5973
Network Mass Selective Detector. High-resolution mass spectra
16
11
and
co-workers
recently
reported
that
3-alkyl-3-
methoxycarbonyl-2-oxindoles can be transformed into the
corresponding 3-hydroxy derivatives, by treatment with NaH and
an oxygen balloon. In our case the reaction of compounds 4
with 1 equiv of LiOEt in THF at rt under air atmosphere gave the
corresponding 3-alkyl-3-hydroxy-2-oxindoles in good yields
12
(GC-EI) were recorded using a QTOF Agilent 7200 instrument
for the exact mass and Agilent 7890B for the GC. Analytical
TLC was performed using ALUGRAM® Xtra SIL G/UV254
silica gel plates, and the spots were determined under UV light
(
Table 4).
a
(λ=254 nm). Allylic alcohols were purchased as pure E-
Table 4. Synthesis of 3-alkyl-3-hydroxy-2-oxindoles 6.
stereoisomers.
4
.2. General procedure for the synthesis of 3-acetyl-3-allyl-2-
oxindoles 2.
To a round-bottom flask was added Pd(dba) (3 mol%, 5.2
2
mg, 0.009 mmol), rac-BINAP (3 mol%, 5.6 mg, 0.009 mmol),
and dry THF (1.5 mL) and the mixture stirred for 30 min. Then,
the oxindole 1 (0.3 mmol), the BINOL derived phosphoric acid
1
2
3
Yield
b
Entry
R
R
R
Product
(3 mol%, 3.1 mg, 0.009 mmol) and allyl alcohol (31 µL, 0.45
(
%)
mmol) were added. The resulting mixture was stirred at rt for 60
h, and afterwards extracted with EtOAc (3x10 mL) and the
organic phases washed with H O (10 mL), dried (MgSO ) and
evaporated to dryness. The residue was purified by flash
chromatography (EtOAc/hexane) affording pure products 2.
Me
Bn
6aa
6ab
6ac
6ad
6ba
6ca
1
2
3
4
5
Me
Me
Me
Me
Me
Bn
H
H
70
68
68
70
57
58
2
4
allyl
H
propargyl
Me
H
OMe
OMe
Me
6
3-Acetyl-3-allyl-1-methylindolin-2-one (2aa): Yield 96%; Orange
a
Reaction conditions: 4 (0.15 mmol), LiOEt (0.15 mmol), THF (1.5
oil; R 0.19 (hexane/EtOAc 9/1); IR (neat) ν : 3521, 3410, 3078,
f
mL), 12 h, rt under air.
-1
1
3
057, 3006, 2923, 1738, 1724, 1609 cm ; H NMR (400 MHz)
δH: 7.36 (td, J = 7.7, 1.3 Hz, 1H), 7.19–7.17 (m, 1H), 7.10 (td, J =
.5, 0.9 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 5.30 (dddd, J = 16.9,
10.1, 7.8, 6.7 Hz, 1H), 5.00 (dq, J = 17.0, 1.3 Hz, 1H), 4.90–4.87
m, 1H), 3.28 (s, 3H), 2.95 (ddt, J = 13.8, 6.7, 1.1 Hz, 1H), 2.86
b
Isolated yield after flash chromatography.
7
3
. Conclusions
(
13
The Pd-catalyzed allylation of 3-acetyl-2-oxindoles with allyl
(dd, J = 13.9, 7.9 Hz, 1H), 1.99 (s, 3H); C NMR (101 MHz) δC:
alcohol can be performed under BINOL-derived phosphoric as
co-catalyst in THF at rt in good yields. This methodology allows
the synthesis of monoallylated 2-oxindoles by in situ
deacetylation with Triton B. For the deacylative allylation of 3-
2
1
00.7, 174.5, 144.3, 131.5, 129.3, 127.0, 124.2, 123.2, 119.5,
08.5, 66.4, 37.5, 26.6; LRMS (EI) m/z (%): 229 (8) (M ), 188
+
(14), 187 (100), 186 (24), 172 (14), 160 (24), 158 (16), 144 (13),
1
2
43 (13), 130 (12), 128 (10); HRMS (ESI): calcd. for C H NO
14 15 2
29.1103; found 229.1101.
acetyl-3-methyl-2-oxindoles
with
allylic
alcohols,
Pd(OAc) /dppp and LiOtBu as base (1.5 equiv) gave the best
2
results affording the corresponding 3,3-disubstituted 2-oxindoles
in moderate to good yields. The mildness of both transformations
allows to prepare no-easily accessible unsymmetrical 3,3-
diallylated-1-methyl-2-oxindoles as has been demonstrated for
compound 7. By treatment of 3-alkyl-3-acetyl-2-oxindoles with
LiOEt under air the corresponding 3-alkyl-3-hydroxy-2-
oxindoles can be easily prepared. These reaction conditions are
very mild, the selective substitution and the high tolerance of the
reagents to many functional groups convert this process in an a
priori useful tool for the synthesis of natural products.
3
6
3
-Acetyl-3-allyl-5-methoxy-1-methylindolin-2-one (2ba): Yield
1%; Orange oil; R 0.10 (hexane/EtOAc 9/1); IR (neat) ν : 3077,
f
-1
1
003, 2941, 2836, 1745, 1729, 1601 cm ; H NMR (400 MHz)
δH: 6.88 (dd, J = 8.5, 2.5 Hz, 1H), 6.82–6.79 (m, 2H), 5.31 (dddd,
J = 16.9, 10.1, 7.8, 6.7 Hz, 1H), 5.04–4.99 (m, 1H), 4.91–4.88
(m, 1H), 3.79 (s, 3H), 3.25 (s, 3H), 2.96–2.83 (m, 2H), 2.00 (s,
13
3
1
H); C NMR (101 MHz) δ : 200.8, 174.2, 156.4, 137.8, 131.5,
C
28.2, 119.5, 113.8, 111.2, 108.9, 66.8, 55.9, 37.6, 26.7, 26.6;
+
LRMS (EI) m/z (%): 259 (28) (M ), 218 (15), 217 (100), 216
(21), 202 (37), 190 (12), 188 (16), 176 (10), 174 (29), 173 (11),
1
2
44 (18), 115 (21), 77 (11); HRMS (ESI): calcd. for C H NO
15 17 3
59.1208; found 259.1206.
4
4
. Experimental section
.1. General
3
8
3
-Acetyl-3-allyl-1-benzyl-5-methoxyindolin-2-one (2ca): Yield
9%; Pale orange oil; R 0.21 (hexane/EtOAc 9/1); IR (neat) ν :
f
-
1
1
065, 3032, 2922, 2836, 1745, 1723, 1600 cm ; H NMR (300

7
MHz) δ : 7.33–7.27 (m, 5H), 6.78–6.74 (m, 2
A
H
C
),
C
6.6
E
9
P
(d
T
d,
E
J
D
=
MA1.
N
6H
U
),
S
1.
C
66
R
(d
I
,
P
J
T
= 6.7 Hz, 0.3H), 1.52 (d, J = 6.3 Hz, 3H), 1.45
H
8
5
3
2
1
.3, 0.6 Hz, 1H), 5.33 (dddd, J = 16.6, 10.0, 8.0, 6.5 Hz, 1H),
.07 (ddd, J = 17.0, 3.1, 1.2 Hz, 1H), 5.01–4.86 (m, 3H), 3.75 (s,
H), 3.03–2.88 (m, 2H), 2.01 (s, 3H); C NMR (75 MHz) δC:
(s, 0.3H), 1.39 (s, 0.6H), 1.35 (s, 3H), 0.99 (d, J = 6.9 Hz, 0.3H),
0.68 (d, J = 6.7 Hz, 0.5H); C NMR (101 MHz) δ : 180.6, 143.3,
143.2, 139.2, 138.6, 134.0, 134.0, 129.4, 127.9, 127.8, 127.8,
127.7, 127.4, 124.9, 124.2, 123.9, 123.2, 123.2, 123.0, 122.9,
122.4, 122.3, 122.3, 121.1, 117.0, 115.8, 108.1, 107.9, 107.9,
107.8, 51.3, 51.2, 48.6, 48.4, 45.9, 44.9, 41.4, 35.5, 26.2, 22.8,
13
C
13
00.7, 174.3, 156.4, 136.9, 135.7, 131.6, 128.9, 128.2, 127.9,
27.6, 119.8, 113.8, 111.1, 110.1, 66.8, 55.9, 44.3, 37.6, 26.7;
+
LRMS (EI) m/z (%): 335 (10) (M ), 294 (11), 293 (47), 91 (100);
HRMS (ESI): calcd. for C H NO 335.1521; found 335.1521.
22.6, 22.2, 21.6, 18.0, 15.3, 15.0, 13.1; LRMS (EI) m/z (%): 215
21
21
3
+
(10) (M ), 161 (32), 161 (100), 160 (100), 132 (11), 130 (14),
4
.3. Typical procedure for the synthesis of 3-allyl-1-
117 (16) 77 (11), 55 (13); HRMS (ESI): calcd. for C H NO
16 21
215.1310; found 215.1309.
17
methylindolin-2-one (3ab).
After performing the Pd-catalyzed allylation of compound 1a
see, Section 4.2), a solution of benzyltrimethylammonium
hydroxide (Triton B) in MeOH (40 wt%, 136µL, 0.3 mmol) was
added and, immediately, acetic acid (0.85 mL, 15 mmol).
Immediately, the extractive work-up was performed with EtOAc
(
E)-3-(3,7-Dimethylocta-2,6-dien-1-yl)-1,3-dimethylindolin-2-
(
one (5af): Yield 45%; Pale yellow oil; R 0.32 (hexane/EtOAc
9
f
-
1 1
/1); IR (neat) ν : 3055, 2967, 2927, 1713, 1613 cm ; H NMR
(400 MHz) δ : 7.27–7.22 (m, 1H), 7.21–7.17 (m, 1H), 7.03 (td, J
H
=
7.5, 0.9 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 5.00–4.93 (m, 1H),
.89–4.82 (m, 1H), 3.19 (s, 3H), 2.47 (d, J = 7.6 Hz, 2H), 1.95–
(
3x10 mL), the organic phases were washed with H O (10 mL),
2
4
1
3
1
2
dried with MgSO , filtered and concentrated. The resulting crude
4
.82 (m, 4H), 1.64 (s, 3H), 1.54 (s, 3H), 1.50 (s, 3H), 1.37 (s,
was purified by flash chromatography (hexane/EtOAc) to afford
pure compound 3ab in 61% yield.
13
H); C NMR (101 MHz) δ : 180.8, 143.3, 138.9, 134.2, 131.5,
C
27.7, 124.3, 123.1, 122.3, 118.3, 107.8, 48.7, 39.9, 36.8, 26.8,
6.2, 25.8, 22.4, 17.8, 16.4; LRMS (EI) m/z (%): 297 (1) (M ),
+
4
.4. General procedure for the Pd-catalyzed deacylative
162 (11), 161 (100), 160 (30), 130 (8), 117 (8), 69 (27); HRMS
(ESI): calcd. for C20 27NO 297.2093; found 297.2093.
allylation of compounds 4. Synthesis of 3-allylated 3-methyl-
H
2
-oxindoles 5.
(
E)-1,3-Dimethyl-3-(penta-2,4-dien-1-yl)indolin-2-one
(5ag):
To a mixture of Pd(OAc) (3 mol%, 2.0 mg, 0.009 mmol) and
,3-bis(diphenylphosphino)propane (3 mol%, 3.7 mg, 0.009
2
Mixture of isomers (major trans isomer); Yield 55%; Pale yellow
wax; R 0.24 (hexane/EtOAc 9/1); IR (KBr) ν : 2924, 2852, 1713,
1
1
=
5
7
1
4
1
1
f
-
1
1
mmol), was added dry THF (1 mL) under Ar and stirring
continued for 30 min. This mixture was added to a solution of
oxindole 4 (0.3 mmol) in dry THF (0.5 mL). Finally, the allylic
alcohol (0.45 mmol) was added and the mixture was degassed by
three cycles of freeze-pump-thaw and filled with Ar before the
addition of LiOtBu (36 mg, 0.45 mmol). The solution was stirred
at rt for 14 h and then extracted with EtOAc (3x10 mL). The
organic phases were washed with water (10 mL), dried over
612 cm ; H NMR (300 MHz) δ : 7.26 (td, J = 7.9, 1.3 Hz,
H
H), 7.21–7.16 (m, 1H), 7.06 (td, J = 7.5, 1.0 Hz, 1H), 6.83 (d, J
7.8 Hz, 1H), 6.21–5.96 (m, 2H), 5.36 (dt, J = 15.0, 7.7 Hz, 1H),
.09–5.02 (m, 1H), 4.96–4.92 (m, 1H), 3.19 (s, 3H), 2.53 (d, J =
13
.7 Hz, 2H), 1.37 (s, 3H); C NMR (75 MHz) δ : 180.2, 143.2,
C
36.7, 134.8, 133.7, 128.3, 127.9, 123.0, 122.5, 116.3, 108.0,
8.5, 41.3, 26.2, 22.7; LRMS (EI) m/z (%): 227 (5) (M ), 174 (9),
61 (13), 160 (100), 132 (11), 130 (13), 117 (15), 77 (10), 67
+
MgSO , and evaporated under vacuum. The pure compounds 5
4
(10); HRMS (ESI): calcd. for C H NO 227.1310; found
15 17
2
were obtained after flash chromatography (hexane/EtOAc).
27.1305.
18
11
19
19
11
18
14
Compounds 5aa, 5ac, 5ae, 5’ae, 5ai, 5aj, 5ba and
12
5
ca are known, new compounds follow:
1
7
3
7
1
1
4
,3-Dimethyl-3-(penta-1,4-dien-3-yl)indolin-2-one (5ag’): Yield
%; Colorless oil; R 0.28 (hexane/EtOAc 9/1); IR (neat) ν :
(
7
3
E)-3-(Hex-2-en-1-yl)-1,3-dimethylindolin-2-one (5ab): Yield
f
-
1
1
076, 2962, 2926, 1712.8, 1613 cm ; H NMR (300 MHz) δ :
0%; Yellow oil; R 0.17 (hexane/EtOAc 9.5/0.5); IR (neat) ν :
H
f
-
1
1
.31–7.25 (m, 1H), 7.22–7.20 (m, 1H), 7.05 (td, J = 7.5, 1.0 Hz,
H), 6.82 (d, J = 7.8 Hz, 1H), 5.86 (ddd, J = 17.0, 10.4, 8.3 Hz,
H), 5.39 (ddd, J = 17.1, 10.2, 8.7 Hz, 1H), 5.19–5.01 (m, 3H),
.93 (dd, J = 10.1, 1.9 Hz, 1H), 3.22–3.14 (m, 4H), 1.36 (s, 3H)
055, 2962, 2927, 2872, 1713, 1613 cm ; H NMR (400 MHz)
δC: 7.27–7.23 (m, 1H), 7.19–7.16 (m, 1H), 7.05 (td, J = 7.5, 0.9
Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 5.40–5.32 (m, 1H), 5.08–4.99
m, 1H), 3.18 (s, 3H), 2.50–2.39 (m, 2H), 1.81 (q, J = 7.0 Hz,
(
13
ppm; C NMR (CDCl , 75 MHz) δ : 179.9, 143.7, 135.7, 135.6,
2
3
1
1
H), 1.35 (s, 3H), 1.20 (q, J = 7.3 Hz, 2H), 0.73 (t, J = 7.4 Hz,
3
C
13
1
2
1
32.4, 128.0, 123.7, 122.3, 118.2, 117.4, 107.9, 55.6, 51.2, 26.2,
H); C NMR (101 MHz) δ : 180.5, 143.3, 134.9, 134.0, 127.7,
C
+
1.8; LRMS (EI) m/z (%): 227 (5) (M ), 161 (11), 160 (100),
23.9, 123.0, 122.3, 107.9, 48.7, 41.5, 34.5, 26.1, 22.6, 22.5,
+
32 (10), 130 (11), 117 (13), 77 (7), 67 (5), 65 (5); HRMS (ESI):
3.5; LRMS (EI) m/z (%): 243 (8) (M ), 162 (9), 161 (80), 160
calcd. for C H NO 227.1310; found 227.1309.
(
100), 130 (8), 117 (9); HRMS (ESI): calcd. for C H NO
15 17
16
21
2
43.1623; found 243.1621.
3
-(Cyclohex-2-en-1-yl)-1,3-dimethylindolin-2-one
(5ah):
Mixture of diastereoisomers; Yield 55%; Pale yellow oil; R 0.28
(
E)-3-(But-2-en-1-yl)-1,3-dimethylindolin-2-one
(5ad)
and
f
(
2
3
hexane/EtOAc 9/1); IR (Major diastereoisomer, neat) ν : 2930,
isomers: Yield 45%; Brown oil; R 0.22 (hexane/EtOAc 9/1); IR
f
-
1 1
-
1
1
866, 1712, 1611 1492.6, cm ; H NMR (major diastereoisomer,
00 MHz) δ : 7.29–7.23 (m, 1H), 7.21–7.18 (m, 1H), 7.02 (td, J
(neat) ν : 3054, 3025, 2965, 2927, 1716, 1613 cm ; H NMR
(400 MHz) δ : 7.29–7.24 (m, 1.7H), 7.21 (d, J = 7.3 Hz, 0.3H),
H
H
=
7.5, 1.0 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 5.88–5.74 (m, 2H),
7
7
0
.17 (d, J = 7.3 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1.5H), 6.83 (d, J =
.7 Hz, 1.4H), 5.87 (dt, J = 17.3, 9.4 Hz, 0.2H), 5.67–5.54 (m,
.3H), 5.42 (dq, J = 12.8, 6.3 Hz, 1H), 5.16–4.99 (m, 1.4H), 4.90
3
.21 (s, 3H), 2.72–2.63 (m, 1H), 1.95–1.72 (m, 2H), 1.64–1.33
1
3
(m, 6H), 0.95–0.83 (m, 1H); C NMR (major diastereoisomer,
7
1
5 MHz) δ : 180.5, 143.7, 133.1, 130.8, 127.7, 126.0, 123.8,
22.3, 107.7, 51.0, 43.0, 26.2, 25.1, 24.5, 21.8, 21.5; LRMS (EI)
(d, J = 10.1 Hz, 0.1H), 3.24 (s, 0.4H), 3.22 (s, 0.7H), 3.20 (s,
C
3
H), 3.18 (s, 0.3H), 2.70–2.47 (m, 0.7H), 2.43 (d, J = 7.2 Hz,

8
Tetrahedron
1), MA
+
m/z (%): 241 (8) (M ), 162 (20), 161 (100), 1
A
60
C
(7
C
3)
E
, 1
P
3
T
0
E
(1
D
R
N
efe
U
re
S
nc
C
es
R
anIP
d notes
T
1
17 (11), 81 (22); HRMS (ESI): calcd. for C H NO 241.1467;
16
19
found 241.1464.
1
2
.
.
For a review, see: Muzart J. Eur. J. Org. Chem. 2007; 3077-3089.
For a review, see: Weaver JD, Recio AIII, Grenning AJ, Tunge JA.
Chem. Rev. 2011; 111: 1846-1913.
4
.5. General procedure for the deacylative oxidation of
3
.
(a) Grenning AJ, Tunge JA. Angew. Chem. Int. Ed. 2011; 50: 1688-
compounds 4. Synthesis of 3-alkyl-3-hydroxy-2-oxindoles 6.
1
1
699; (b) Grenning AJ, Tunge JA. J. Am. Chem. Soc. 2011; 133:
4785-14794; (c) Grenning AJ, Van Allen CK, Maji T, Lang SB,
Tunge JA. J. Org. Chem. 2013; 78: 7281-7287.
To a solution of oxindole 4 (0.15 mmol) in dry THF (1.5 mL)
was added dropwise a solution of LiOEt (0.1 M in THF, 150 µL,
.15 mmol) and the mixture was stirred at rt for 12 h. Then was
extracted with EtOAc (3x10 mL), the organic phases were
4.
(a) Otera J, Ioka S, Nozaki H. J. Org. Chem. 1989; 54: 4013-4014; (b)
Otera J, Dan-oh N, Nozaki H. J. Org. Chem. 1991; 56: 5307-5311; (c)
Orita A, Sakamoto K, Hamada Y, Mitsutome A, Otera J. Tetrahedron
0
1
999; 55: 2899-2910.
5
.
For recent reviews, see: (a) Cao ZY, Wang YH, Zeng YP, Zhou J.
Tetrahedron Lett. 2014; 55: 2571-2584; (b) Shen K, Liu X, Feng X.
Chem. Sci. 2012; 3: 327-334; (c) Singh GS, Desta ZY. Chem. Rev.
washed with water (10 mL), dried over MgSO , and evaporated
4
under vacuum. The pure compounds 6 were obtained after flash
chromatography (hexane/EtOAc).
2
012; 112: 6104-6155; (d) Dalpozzo R, Bartoli G, Bencivenni G.
Chem. Soc. Rev. 2012; 41: 7247-7290; (e) Zhou F, Liu YL, Zhou J.
Adv. Synth. Catal. 2010; 352: 1381-1407; (f) Galliford CV, Scheidt
KA. Angew. Chem. Int. Ed. 2007; 46: 8748-8758.
Trost BM, Brennan MK. Org. Lett. 2006; 8: 2027-2030.
Trost BM, Zhang Y. J. Am. Chem. Soc. 2006; 128: 4590-4591.
Huang A, Kodanko JJ, Overman LE. J. Am. Chem. Soc. 2004; 126:
20
21
22
23
24
Compounds 6aa, 6ab, 6ac, 6ad, and 6ba are known, a
6
7
8
.
.
.
new compound follow:
1
4043-14053.
Trost BM, Malhotra S, Chan WH. J. Am. Chem. Soc. 2011; 133: 7328-
331.
1
-Benzyl-3-hydroxy-5-methoxy-3-methylindolin-2-one
(6ca):
9
1
1
.
Yield 58%; Orange solid; m.p. 135–137 °C (hexane/EtOAc); Rf
0
1
7
.12 (hexane/EtOAc 7/3); IR (KBr) ν : 3347, 3028, 2927, 2833,
0. Linton EC, Kozlowski MC. J. Am. Chem. Soc. 2008; 130: 16162-
16163.
1. (a) Yang H, Zhou H, Yin H, Xia C, Jiang G. Synlett 2014; 25: 2149-
-
1 1
704 cm ; H NMR (400 MHz) δ : 7.32–7.23 (m, 5H), 7.04 (d, J
H
=
2.6 Hz, 1H), 6.70 (dd, J = 8.5, 2.6 Hz, 1H), 6.60 (d, J = 8.5 Hz,
2
2
154; (b) Kumar N, Das MK, Ghosh S, Bisai A. Chem. Commun.
017, 53, 2170-2170.
1
3
1
1
H), 4.93 (d, J = 15.7 Hz, 1H), 4.78 (d, J = 15.7 Hz, 1H), 3.75 (s,
13
H), 3.17 (br s, 1H), 1.67 (s, 3H); C NMR (101 MHz) δC:
78.8, 156.6, 135.6, 135.1, 132.9, 128.9, 127.8, 127.3, 114.2,
12.
Ortega-Martínez A, Molina C, Moreno-Cabrerizo C, Sansano JM,
Nájera C. Synthesis 2017, DOI: 10.1055/s-0036-1590880.
1
3. (a) Tamaru Y, Horino Y, Araki M, Tanaka S, Kimura M. Tetrahedron
Lett. 2000; 41: 5705-5709; (b) Kimura M, Mukai R, Tanigawa N,
Tanaka S, Tamaru, Y. Tetrahedron 2003; 59: 7767-7777.
4. (a) Trost BM, Zhang Y. Chem. Eur. J. 2011; 17: 2916-2922; (b)
Reisch J, Mueller M, Labitzke H. Arch Pharm. 1984; 317: 639-646.
5. (a) Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S,
Nakashima S, Xu F, Yoshikawa M. Bioorg. Med. Chem. 2007; 15:
10.6, 110.3, 74.3, 55.9, 43.9, 25.3; LRMS (EI) m/z (%): 283
+
(
(
39) (M ), 267 (8), 192 (7), 174 (5), 146 (8), 106 (7), 92 (10), 91
100), 89 (6), 77 (7), 65 (19) 63 (5), 51 (5); HRMS (ESI): calcd.
1
1
for C H NO 283.1208; found 283.1203.
17
17
3
1
539-1546; (b) Lucas-López C, Patterson S, Blum T, Straight AF, Toth
4
1
.6. General procedure for the combined double allylation of
a. Synthesis of 3-allyl-3-methallyl-1-methyl-2-oxindole 7.
J, Slawin AMZ, Mitchison TJ, Sellers JR, Westwood NJ. Eur. J. Org.
Chem. 2005; 1736-1740.
1
6. Ohmatsu K, Ando Y, Ooi T. Synlett 2017; 28: 1291-1294 and
references cited therein.
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8. Zhou Y, Zhao Y, Dai X, Liu J, Li L, Zhang H. Org. Biomol. Chem.
2011; 9: 4091-4097.
The first step was carried out following the description of
1
1
section 4.2. for the synthesis of intermediate 2aa. The second
step was run according to section 4.4. and, after purification,
product 7 was isolated in 72% yield.
25
1
9. Zhou B, Hou W, Yang Y, Feng H, Li Y. Org. Lett. 2014; 16: 1322-
1
325.
2
2
0. Shin I, Ramgren SD, Krische MJ. Tetrahedron 2015, 71, 5776-5780.
1. Ghandi M, Feizi S, Ziaie F, Notash B. Tetrahedron 2014; 70: 2563-
2569.
Acknowledgments
2
2
2. Zhao C, Tan Z, Liang Z, Deng W, Gong H. Synthesis 2014; 46: 1901-
1
907.
3. Alcaide B, Almendros P, Rodríguez-Acebes R. J. Org. Chem. 2005;
0: 3198-3204.
We gratefully acknowledge financial support from the
Spanish Ministerio de Economía y Competitividad (MINECO)
7
(projects CTQ2013-43446-P and CTQ2014-51912-REDC), the
24. Wanh H, Li Y, Wang G, Zhang H, Yang SD. Asian J. Org. Chem.
Spanish Ministerio de Economía, Industria y Competitividad,
Agencia Estatal de Investigación (AEI) and Fondo Europeo de
Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P
and CTQ2016-81797-REDC), the Generalitat Valenciana
2013; 2: 486-490.
2
5. Kinthada LK, Medisetty SR, Parida A, Babu KN, Bisai A. J. Org.
Chem. 2017; 82: 8548-8567.
(PROMETEO2009/039 and PROMETEOII/2014/017) and the
University of Alicante. A. O.-M. thanks MINECO for a
predoctoral fellowship.
Supplentary data
Supplementary data associated with this article can be found
in the online version, at http://dx.doi.org/10.1016/j.tet.